Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype

2005 ◽  
Vol 93 (04) ◽  
pp. 700-705 ◽  
Author(s):  
Deepak Voora ◽  
Charles Eby ◽  
Mark Linder ◽  
Paul Milligan ◽  
Bonny Bukaveckas ◽  
...  
Keyword(s):  
Warfarin Therapy ◽  
Adverse Outcome ◽  
Warfarin Dose ◽  
Controlled Study ◽  
Cyp2c9 Genotype ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Dosing Algorithm ◽  
Orthopedic Patients ◽  
Cytochrome P 450

SummaryCytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4–9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R2 = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.

scholarly journals Genetic-based dosing in orthopedic patients beginning warfarin therapy

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1511-1515 ◽  
Author(s):  
Eric A. Millican ◽  
Petra A. Lenzini ◽  
Paul E. Milligan ◽  
Leonard Grosso ◽  
Charles Eby ◽  
...  
Keyword(s):  
Warfarin Therapy ◽  
Smoking Status ◽  
Warfarin Dose ◽  
Therapeutic Index ◽  
International Normalized Ratio ◽  
Narrow Therapeutic Index ◽  
Therapy Initiation ◽  
Estimated Blood Loss ◽  
Epoxide Reductase ◽  
Orthopedic Patients

AbstractHigh variability in drug response and a narrow therapeutic index complicate warfarin therapy initiation. No existing algorithm provides recommendations on refining the initial warfarin dose based on genetic variables, clinical data, and international normalized ratio (INR) values. Our goal was to develop such an algorithm. We studied 92 patients undergoing primary or revision total hip or knee replacement. From each patient we collected a blood sample, clinical variables, current medications, and preoperative and postoperative laboratory values. We genotyped for polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase (VKORC1) genes. Using stepwise regression, we developed a model for refining the warfarin dose after the third warfarin dose. The algorithm explained four fifths of the variability in therapeutic dose (R2adj of 79%). Significant (P > .05) predictors were INR value after 3 doses (47% reduction per 0.25-unit rise), first warfarin dose (+7% per 1 mg), CYP2C9*3 and CYP2C9*2 genotype (−38% and −17% per allele), estimated blood loss (interacting with INR3), smoking status (+20% in current smokers), and VKORC1 (−11% per copy of haplotype A). If validated, this model should provide a safer, more effective process for initiating warfarin therapy.

Balloon-assisted maturation of autogenous arteriovenous fistulae: A randomized controlled prospective study

Vascular ◽  
2020 ◽  
pp. 170853812097987
Author(s):  
Mohammed Elkassaby ◽  
Nashaat Elsaadany ◽  
Khaled Mowaphy ◽  
Mosaad Soliman
Keyword(s):  
Controlled Study ◽  
Complication Rates ◽  
Arteriovenous Fistulae ◽  
Early Maturation ◽  
Randomized Controlled ◽  
Functional Maturation ◽  
Increased Risk ◽  
Group A ◽  
Group B

Background Current guidelines recommend referral of patient with renal failure for access creation 6 months before planned dialysis. There is a growing cohort of patients that require long-term hemodialysis without adequate preparation. Temporary dialysis catheters and rapid access arteriovenous grafts (AVG) are far from being an ideal solution in this scenario. In an effort to expedite maturation of autogenous arteriovenous fistulae (AVF), balloon-assisted maturation (BAM) was advised by some authors. This technique still lacks the support of high-level evidence studies. We investigated the ability of intra-operative BAM to induce early functional maturation of AVFs. Methods This is a prospective randomized controlled study conducted in a tertiary referral center, with a catchment area of more than 15 million population. Cases were divided into two groups; Group (A), where BAM technique was performed, while in the control group (B), the standard technique was used (NO BAM) for creation of AVFs. Results Between June 2017 and May 2019, 300 cases were recruited from a total of 648 primary AVF creation instances. Patients’ age ranged from 19 to 89 (mean 51.17 ±SD 15.5) years. Group A (BAM) included 52.3% ( n = 157) AVFs, while Group B included 47.7% ( n = 143) AVFs. The average maturation time was 3.7 weeks (SD ± 1.3, 95% CI 3.55–3.95) and 5.91 weeks (SD ± 2.2, 95% CI 5.55–6.26) for both groups, respectively ( p = 0.0001). 78.3% of the AVFs that underwent BAM showed early maturation within 2–4 weeks vs 32.2% only in the NO BAM group ( p = 0.002). Successful functional maturation was higher among cases of the BAM group (93%), compared to the NO BAM group (77%) ( p = 0.001). Complication rates were 9.6% and 4.9% in the two groups, respectively ( p = 0.042). Conclusion BAM can play a pivotal role in helping the dialysis society meet the goals of the Fistula First Initiative, keeping in mind that this comes with an increased risk of complications. BAM should be considered only when unplanned early access to long-term dialysis is required.

scholarly journals A Multi-Institutional Randomized Controlled Trial to Investigate Whether Zoledronate Prevents Bone Loss After Discontinuation of Denosumab: The Study Protocol of Denosumab Sequential Therapy (DST) Trial

2021 ◽  
Vol 8 ◽  
Author(s):  
Chia-Che Lee ◽  
Chen-Yu Wang ◽  
Chih-Chien Hung ◽  
Chuan-Ching Huang ◽  
Chung-Yi Li ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Bone Loss ◽  
Controlled Trial ◽  
Rebound Effect ◽  
Sequential Therapy ◽  
Drug Holiday ◽  
Controlled Study ◽  
Mineral Density ◽  
Randomized Controlled ◽  
Increased Risk

Background: Though denosumab is an effective treatment for osteoporosis, the rebound effect after discontinuation has drawn investigators' attention. It includes a dramatic loss of gained bone mineral density (BMD) and an increased risk of vertebral fractures. This prospective multi-institutional randomized controlled trial aims to investigate whether zoledronate prevents loss of BMD after discontinuation of denosumab. The trial was registered as Denosumab Sequential Therapy (DST) trial in March 2019 at clinicaltrials.gov, with the identifier NCT03868033.Methods: The study is conducted at National Taiwan University Hospital and its branches. Patients who have continuously received denosumab treatment for two or more years are surveyed for eligibility. Baseline characteristics and questionnaires of life quality are recorded after recruitment. BMD, circulating levels of bone turnover markers (BTMs), including serum N-terminal propeptide of type 1 collagen (P1NP) and C-terminal telopeptide (CTX), are checked before the stratified randomization to 4 groups. Biological sex and the T-scores are used to create 4 strata. The participants in group 1 adhere to regular denosumab therapy for another 2 years. All the other patients receive on-time zoledronate treatment in the first year. The participants in group 2, 3, and 4 have on-time denosumab, on-time zoledronate and drug holiday in the second year, respectively. BMDs are checked annually. Pre-scheduled checkpoints of BTMs are also arranged. For patient safety, rescue treatment with another injection of zoledronate will be applied to the patients on drug holiday if the CTX levels raise above the pre-specified threshold, 0.573 ng/mL for women and 0.584 ng/mL for men. The primary outcomes are the percentage changes of BMDs in lumbar spine, total hip and femoral neck. The secondary outcomes include the changes of serum level of the BTMs, new osteoporotic fractures, extra zoledronate injections needed in group 4 and the differences of quality of life.Discussion: We aim to provide evidence whether zoledronate prevents bone loss after denosumab cessation. To our knowledge, the study has the largest sample size. No other randomized controlled study included all the three different treatment strategies and a positive control. It is also the first associated randomized controlled trial outside Europe.

Effect of Polymorphisms in the Cytochrome P450 CYP2C9 Gene on Warfarin Anticoagulation

2004 ◽  
Vol 128 (12) ◽  
pp. 1360-1363
Author(s):  
Dorothy M. Adcock ◽  
Charles Koftan ◽  
Domnita Crisan ◽  
Frederick L. Kiechle
Keyword(s):  
Warfarin Therapy ◽  
Standard Dose ◽  
Initial Period ◽  
Warfarin Dose ◽  
Interindividual Variation ◽  
Bleeding Complications ◽  
Cyp2c9 Genotype ◽  
Cyp2c9 Gene ◽  
Variant Alleles ◽  
The Relationship

Abstract Context.—Warfarin is a widely used anticoagulant with efficacy in treatment and prevention of thrombosis. Patient management, however, is difficult because of interindividual variation in response to standard doses due to significant differences in metabolic rates. Warfarin metabolism is under genetic control, involving primarily the CYP2C9 gene encoding the enzyme that catalyzes the conversion of warfarin to inactive metabolites. Objective.—Several polymorphisms of CYP2C9 have been reported; the variant alleles *2 and *3 have decreased enzymatic activity. The objective of this case study is to investigate the relationship between CYP2C9 genotype and warfarin anticoagulation. Design.—A case of deep vein thrombosis treated with the standard warfarin dose is investigated for intensity of anticoagulation and CYP2C9 genotype; the case illustrates the relationship between CYP2C9 variant and overanticoagulation with subsequent bleeding complication. Results.—The patient's genotype, CYP2C9*1*3, correlated with an exaggerated anticoagulant response during the initiation of warfarin therapy at standard dose, and a bleeding episode ensued. Based on heterozygosity for the *3 variant allele, it was recommended that the patient be maintained on a low-dose warfarin regimen. Conclusions.—The practical implications of identifying genetic risk factors that lead to overanticoagulation are multiple. Genotype knowledge of the CYP2C9 variant alleles may help the clinician to individualize warfarin therapy with the ultimate goals of shortening the initial period of induction therapy, reaching a stable maintenance dose earlier, and minimizing bleeding complications in patients who are high responders and need lower warfarin doses.

scholarly journals Warfarin Interaction With Hepatic Cytochrome P-450 Enzyme-Inducing Anticonvulsants

2017 ◽  
Vol 24 (1) ◽  
pp. 172-178 ◽  
Author(s):  
Nathan P. Clark ◽  
Kim Hoang ◽  
Thomas Delate ◽  
John R. Horn ◽  
Daniel M. Witt
Keyword(s):  
Warfarin Therapy ◽  
Therapeutic Response ◽  
Warfarin Dose ◽  
Clinical Information ◽  
International Normalized Ratio ◽  
The Mean ◽  
Warfarin Dosing ◽  
Meaningful Interaction ◽  
Cytochrome P 450 ◽  
Hepatic Cytochrome

Initiation of cytochrome P-450 (CYP)-inducing anticonvulsant medications during warfarin therapy may decrease anticoagulant effect and necessitate frequent warfarin dose adjustments to maintain therapeutic response measured by the international normalized ratio (INR). Clinical information regarding interactions between warfarin and these medications is limited. This study investigated warfarin dose and INR response following CYP-inducing anticonvulsant initiation among chronic warfarin users. This retrospective, pre-post study included patients ≥18 years who were receiving chronic warfarin therapy and who initiated carbamazepine, oxcarbazepine, phenobarbital, or phenytoin between January 1, 2006, and December 31, 2013. Mean weekly warfarin dose/INR ratio and mean weekly warfarin dose were compared in the 90 days pre- and days post-anticonvulsant initiation periods. Of the 57 included patients, 34 (60%), 15 (26%), 6 (11%), and 2 (3%) patients purchased a prescription for carbamazepine, phenytoin, oxcarbazepine, and phenobarbital, respectively. Mean age was 70 years, 59% were female, and the majority were receiving chronic warfarin therapy for atrial fibrillation (39%) or venous thromboembolism (26%). The ratio of mean warfarin dose and INR increased significantly between the pre- and post-anticonvulsant initiation periods (from 13 mg/INR to 18 mg/INR, respectively, P ≤ .001) as did the mean weekly warfarin dose (from 33 mg to 37 mg, P = <.001). Warfarin dose and dose/INR ratio significantly increased after carbamazepine initiation (both P < .001), while oxcarbazepine, phenobarbital, and phenytoin initiation did not significantly affect warfarin dosing. Our results support the presence of a clinically meaningful interaction between warfarin and carbamazepine. Frequent INR monitoring and warfarin dose escalation are recommended in this setting.

Existing Warfarin Therapy in Long-Term Care Facilities Maybe Inadequate.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4160-4160
Author(s):  
Bahareh Motlagh ◽  
Madeleine M. Verhovsek ◽  
Alexandra Papaioannou ◽  
Crowther Mark ◽  
Lisa Dolovich ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Elderly Patients ◽  
Warfarin Therapy ◽  
Long Term Care ◽  
The Elderly ◽  
Term Care ◽  
Increased Risk ◽  
Dosing Algorithm ◽  
Care Facilities

Abstract Despite evidence-based guidelines derived from large clinical trials supporting the use of warfarin for stroke prophylaxis, studies in elderly patients have shown that oral anticoagulants are not used optimally. The risk associated with inappropriate use is compounded by the observation that the elderly are at enhanced risk of thromboembolic complications compared with younger atrial fibrillation patients. All patients with atrial fibrillation who do not have a contraindication to warfarin, and who meet inclusion criteria, should be treated with warfarin to achieve a target International Normalized Range (INR) of 2.5 (range 2.0–3.0). INR levels of 2.0–3.0 have been shown to be relatively safe and more efficacious than lower target INR values in all age groups including the elderly. Patients with INR values below this range remain at increased risk of thrombosis, while those with INR values above the given range are at increased risk of bleeding. The primary objective of this study was to determine the achieved intensity of warfarin therapy in a cohort of patients living at long-term care facility. In such facilities optimal anticoagulation should be achievable, since laboratory monitoring, dose adjustment, and compliance can be achieved. In this study, data were collected on physicians’ warfarin prescribing practices as well as INR levels of 108 residents in five long-term care facilities in the Hamilton-Wentworth area over a period of 12 months. In total, 3146 INR values, extending over 28,256 patient-days of monitoring, were analyzed. Indications for warfarin were atrial fibrillation, transient ischemic attack, pulmonary embolus, cardiac valve replacement, myocardial infarction, and deep vein thrombosis. In general, the warfarin dosage was not determined using an established dosing algorithm. Our findings revealed that LTC residents spent approximately 40 percent of the time with INR values below 2.0. We therefore conclude, that the overall quality of anticoagulant therapy in long-term care patients may be inadequate. Our observations suggest that organized dosing algorithms may be of benefit in such settings, however this hypothesis needs to be confirmed in prospective studies. For this purpose we plan to implement a warfarin dosing algorithm in order to determine whether the percentage of time spent within the therapeutic INR range can be improved.

scholarly journals Maternal PCOS status and metformin in pregnancy: Steroid hormones in 5–10 years old children from the PregMet randomized controlled study

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257186
Author(s):  
Liv Guro Engen Hanem ◽  
Øyvind Salvesen ◽  
André Madsen ◽  
Jørn V. Sagen ◽  
Gunnar Mellgren ◽  
...  
Keyword(s):  
Free Testosterone ◽  
Reference Population ◽  
Controlled Study ◽  
Z Score ◽  
Follow Up Study ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Z Scores ◽  
In Pregnancy

Objective Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels. Design This is a follow-up study of 5–10 years old children from the PregMet-study–a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included. Methods There was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints. Results Girls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14–1.17), p = 0.014). Conclusion Maternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty.

scholarly journals Role of CYP2C9, VKORC1 and Calumenin Genotypes in Monitoring Warfarin Therapy: An Egyptian Study

2013 ◽  
Vol 1 (1) ◽  
pp. 76-82
Author(s):  
Naguib Zohir ◽  
Reham Afifi ◽  
Asmaa Ahmed ◽  
Zinab Aly ◽  
Mehry Elsobekey ◽  
...  
Keyword(s):  
Anticoagulant Therapy ◽  
Warfarin Therapy ◽  
Oral Anticoagulant Therapy ◽  
Warfarin Dose ◽  
Wild Type ◽  
Pcr Rflp ◽  
Type Gene ◽  
Cytochrome P 450 ◽  
Insitu Hybridization

Background: Oral anticoagulant therapy is conditioned by environmental and genetic factors.Objectives: To verify the effect of the calumenin, cytochrome P-450 variants and VKORC1 genetic polymorphisms on the response to warfarin therapy and warfarin dose adjustment.Patients and Methods: We selected fifty warfarin treated patients with dose adjusted at INR value between 2 and 3. PCR-RFLP is used for of calumenin gene polymorphism. Insitu Hybridization was used for identification of VKORC1 promoter and CYP2C9 variants polymorphisms.Results: The warfarin dose in the patients with Calumenin and CYP2C9 genetic polymorphism was lower than the wild type gene. The warfarin dose in the patients with VKORC1 variants was statistically lower compared to that of the wild-type. The presence of combined CYP2C9 genetic variants and VKORC1 polymorphism was associated with lower warfarin dose than that the wild types.Conclusion: Calumenin (CALU) might be a new genetic factor involved in the pharmacogenetics of anticoagulant therapy.

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